Articular cartilage of higher animals, including man, has very limited potential for repair. Following injuries to articular cartilage, the cartilage generally does not repair itself because of its very limited capacity for regeneration. Repair is dependent on the extent and the depth of injury and the surviving chondrocytes and normal articular cartilage matrix. In injuries involving subchondral bone, there is no regeneration of the cartilage, but there is typically enlargement and progression of the lesion with associated pain. The ultimate goal of treatment of these lesions is restoration of the cartilage, but in most cases this is not achieved.
Adult articular cartilage is not vascularized and, as stated above, lacks the capacity to regenerate itself after sustaining damage (Vangness, C. T., Jr. et al., Am. J. Orth. 33, No. 25S: 29, 2004). When cartilage is cut, without involvement of subchondral bone, the defect often will persist for the duration of the individual's life.
Treatment of articular cartilage defects may be either surgical or non-surgical. Several operative procedures are currently used to repair or remove damaged cartilage in order to prevent further destruction of the joint, decrease pain, and restore function. These include arthroscopic debridement and lavage, subchondral bone stimulating procedures, transplantation of chondrocytes or cartilage autografts and allografts and total knee arthroplasty. However, none of these produces regeneration of the native articular cartilage.
Arthroscopic abrasion arthroplasty was developed as an alternative to open debridement procedures. However, it is not a cartilage repair procedure, but rather merely removes frayed cartilage components as a palliative approach that may delay or defer unicondylar or total knee arthroplasty. The latter, replaces articular surfaces with metal or polyethylene (or similar plastic or ceramic) components. This technique is irreversible and precludes any cartilage regeneration (Johnson, L. L., Clin. Orth. 391S: 306-317, 2001).
Drilling of subchondral bone or microfracture of the same has been used to provide blood supply to fibrocartilage covering of subchondral bone. However, this does not result in regeneration of articular hyaline cartilage.
Tissue and cartilage cell transplantation has the potential to produce cartilage repair at the expense of transplanted cells or intact cartilage. To achieve cartilage repair, transplanted cells and tissues must participate in the development of a permanent three-dimensional matrix. In addition, the cells and tissue must incorporate themselves within the host cartilage.
Several tissue transplantation techniques have been used to treat articular cartilage defects including autologous chondrocytes or mesenchymal cells. Autologous chondrocyte transplantation involves removing a portion of normal articular cartilage from a non-weight bearing portion of the joint. The chondrocytes from this cartilage are segregated and placed in tissue culture. The cells proliferate and produce an adequate number of chondrocytes for reimplantation. Subsequently, the original defect is debrided, covered with a periosteal cover (Crites, B. M., Cur. Opinions in Orthopaedics 15: 45, 2004). In the studies to date most successful outcomes have been with circumscribed defects of the knee (Lindahl, A., et al., Novartis Found. Sympos. 249: 175, 2003). This technique is limited by the size of the defect and by the amount of healthy cartilage that can be harvested from a given patient. It does not induce regeneration of cartilage, but repopulated the defect with new cells from a different site.
Osteochondral grafts depend on the healing of the junctions between the graft and the recipient. A drawback of the technique is the necessity to anatomically match the curvature and size of the graft with the defect in the recipient. The technique does not produce regeneration of the native cartilage, but depends on obliterations of the defect either with autologous or allogeneic osteochondral grafts.
Bone morphogenetic proteins (BMP's) have been implicated in cartilage repair, as have been other growth factors. However, to date, application of various BMP's to chondral defects has failed to produce full-thickness repair and regeneration. At best, partial healing of full-thickness articular cartilage defects have been reported in a dog. Most other studies of articular cartilage regeneration have been performed on rodents, and none of these has produced complete articular cartilage regeneration.
The present invention provides for ameliorating at least some of the disadvantages of the prior art. These and other advantages of the present invention will be apparent from the description as set forth below.